Hepatitis C virus is both difficult to treat and a significant cause of morbidity and mortality. It is not understood how hepatitis C establishes infection nor how some patients clear infection. To this end 83 humans exposed to hepatitis C were studied in protocol 00-DK-0221. The immune response (both antibody and T cell) was closely followed and is being characterized. The study is in collaboration with Dr. Rehermann. As an extension of this 28 patients with acute hepatitis C have been followed and treated as indicated. Their clinical course, virological parameters, and T cell responses have been carefully defined. This is in collaboration with Dr. Rehermann. All patients except three have cleared virus, either spontaneously or with treatment. Two of those who did not clear relapsed after therapy and are co-infected with HIV. The third non-responder started treatment in the chronic phase when response rates are lower than during the acute phase. [unreadable] [unreadable] To further understand the virological determinants of infection and the development of chronicity, the hepatitis C virus sequence in the early stages of infection is being determined from the same patients. In particular the sequencing effort is focused on the viral sequence before and after treatment, in the two patients who were HIV positive and relapsed.[unreadable] [unreadable] Once chronicity has been established treatment response rates decrease significantly. One of the hallmarks of the hepatitis C virus is its sequence diversity, which is used to classify hepatitis C into different genotypes. Different genotypes have different response rates to treatment. Response rates are typically higher in genotype 2/3. Protocol 03-DK-0136 studies the response of patients with chronic hepatitis C, genotypes 2 or 3, to a decreased dose of pegylated interferon in combination with ribavirin. A low-dose of peginteferon alfa2a 90mcg/w was given with 800mg/d of ribavirin for 24 weeks to 31 patients of whom 20 (65%) had a sustained virological response. 4 patients who relapsed after treatment and 3 patients who never responded were retreated with the standard dose of 180mcg/week and ribavirin 800mg/d for 48 weeks; only one previous non-responder failed to respond to the extended course. Thus, 26 of 31 patients (84%) achieved an SVR. As the sustained virological response in the low-dose group was lower than expected, patients since then have been treated with the standard dose of peginterferon and ribavirin. So far, 23 patients have been recruited to the standard dose arm. 17 patients finished at least 24 weeks of follow-up post-treatment, 13 of whom (77%) achieved an sustained virological response. 2 patients finished 24 weeks of treatment, both were HCV RNA negative at the end of treatment. Currently 4 patients are still being treated (3 naive patients and one who relapsed after 24 weeks were completed) - all are currently HCV-RNA negative. The initial aim of the treatment of chronic hepatitis C genotype 2/3 study was to use lower doses of medicines in order to lower side effects and still obtain adequate response rates. The doses chosen did not give adequate response rates. A second aim of the study was to define the viral kinetics in the early stages of treatment. This is being done for both doses. The importance of viral kinetics is that it may give insights into the biology of treatment response and allow prediction of response.[unreadable] [unreadable] A second type of chronic hepatitis studied is hepatitis D. Hepatitis D is the most aggressive form of viral hepatitis as well as the most difficult to treat. Interferon therapy is the standard approach. Patients are typically treated for 6 months to a year. Relapse after cessation of therapy is the norm. In protocol 01-DK0247 patients are treated with peginterferon for 5 years. The dose is titrated to maintain normal ALT and minimize side effects. Patients are evaluated before initiating therapy, and after 1, 3, and 5 years. Patients are excluded if they do not meet protocol-defined criteria for response at the 1 year evaluation. Enrollment was planned for 10 - 20 patients. Thirteen patients have been enrolled, and of the 12 who have had one-year evaluations 10 have met the protocol definition of response. Four patients have had their end of 3 year evaluation, 4 have been excluded (one non-compliant, one lost to follow up and only a partial responder, one non-responder, and one death secondary to hepatocellular carcinoma), two have developed antibody to HBs, a protocol end point, and 3 are in their second or third year of therapy. The primary end point of the study is the evaluation after three years although it is planned to treat patients for 5 years.